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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.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
The determination of the spin state of iron-bearing compounds at high pressure and temperature is crucial for our understanding of chemical and physical properties of the deep Earth. Studies on the relationship between the coordination of iron and its electronic spin structure in iron-bearing oxides, silicates, carbonates, iron alloys, and other minerals found in the Earth's mantle and core are scarce because of the technical challenges to simultaneously probe the sample at high pressures and temperatures. We used the unique properties of a pulsed and highly brilliant x-ray free electron laser (XFEL) beam at the High Energy Density (HED) instrument of the European XFEL to x-ray heat and probe samples contained in a diamond anvil cell. We heated and probed with the same x-ray pulse train and simultaneously measured x-ray emission and x-ray diffraction of an FeCO3 sample at a pressure of 51 GPa with up to melting temperatures. We collected spin state sensitive Fe K beta(1,3) fluorescence spectra and detected the sample's structural changes via diffraction, observing the inverse volume collapse across the spin transition. During x-ray heating, the carbonate transforms into orthorhombic Fe4C3O12 and iron oxides. Incipient melting was also observed. This approach to collect information about the electronic state and structural changes from samples contained in a diamond anvil cell at melting temperatures and above will considerably improve our understanding of the structure and dynamics of planetary and exoplanetary interiors.
Kleine Geschichte Spaniens
(2004)
The “HPI Future SOC Lab” is a cooperation of the Hasso Plattner Institute (HPI) and industry partners. Its mission is to enable and promote exchange and interaction between the research community and the industry partners.
The HPI Future SOC Lab provides researchers with free of charge access to a complete infrastructure of state of the art hard and software. This infrastructure includes components, which might be too expensive for an ordinary research environment, such as servers with up to 64 cores and 2 TB main memory. The offerings address researchers particularly from but not limited to the areas of computer science and business information systems. Main areas of research include cloud computing, parallelization, and In-Memory technologies.
This technical report presents results of research projects executed in 2017. Selected projects have presented their results on April 25th and November 15th 2017 at the Future SOC Lab Day events.
This review presents recommended nomenclature for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), a rapidly growing class of natural products. The current knowledge regarding the biosynthesis of the >20 distinct compound classes is also reviewed, and commonalities are discussed.
We present a study of the local atomic environment of the oxygen atoms in the aqueous solutions of NaOH and HCl under simultaneous high-temperature and high-pressure conditions. Experimental nonresonant X-ray Raman scattering core-level spectra at the oxygen K-edge show systematic changes as a function of temperature and pressure. These systematic changes are distinct for the two different solutes and are described well by calculations within the Bethe- Salpeter formalism for snapshots from ab initio molecular dynamics simulations. The agreement between experimental and simulation results allows us to use the computations for a detailed fingerprinting analysis in an effort to elucidate the local atomic structure and hydrogen-bonding topology in these relevant solutions. We observe that both electrolytes, especially NaOH, enhance hydrogen bonding and tetrahedrality in the water structure at supercritical conditions, in particular in the vicinity of the hydration shells. This effect is accompanied with the association of the HCl and NaOH molecules at elevated temperatures.
Weltweit verursachen Städte etwa 70 % der Treibhausgasemissionen und sind daher wichtige Akteure im Klimaschutz bzw. eine wichtige Zielgruppe von Klimapolitiken. Gleichzeitig sind Städte besonders stark von möglichen Auswirkungen des Klimawandels betroffen: Insbesondere extreme Wetterereignisse wie Hitzewellen oder Starkregenereignisse mit Überflutungen verursachen in Städten hohe Sachschäden und wirken sich negativ auf die Gesundheit der städtischen Bevölkerung aus. Daher verfolgt das Projekt ExTrass das Ziel, die städtische Resilienz gegenüber extremen Wetterereignissen in enger Zusammenarbeit mit Stadtverwaltungen, Strukturen des Bevölkerungsschutzes und der Zivilgesellschaft zu stärken. Im Fokus stehen dabei (kreisfreie) Groß- und Mittelstädte mit 50.000 bis 500.000 Einwohnern, insbesondere die Fallstudienstädte Potsdam, Remscheid und Würzburg.
Der vorliegende Bericht beinhaltet die Ergebnisse der 14-monatigen Definitionsphase von ExTrass, in der vor allem die Abstimmung eines Arbeitsprogramms im Mittelpunkt stand, das in einem nachfolgenden dreijährigen Forschungsprojekt (F+E-Phase) gemeinsam von Wissenschaft und Praxispartnern umgesetzt werden soll. Begleitend wurde eine Bestandsaufnahme von Klimaanpassungs- und Klimaschutzstrategien/-plänen in 99 deutschen Groß- und Mittelstädten vorgenommen. Zudem wurden für Potsdam und Würzburg Pfadanalysen für die Klimapolitik durchgeführt. Darin wird insbesondere die Bedeutung von Schlüsselakteuren deutlich. Weiterhin wurden im Rahmen von Stakeholder-Workshops Anpassungsherausforderungen und aktuelle Handlungsbedarfe in den Fallstudienstädten identifiziert und Lösungsansätze erarbeitet, die in der F+E-Phase entwickelt und getestet werden sollen. Neben Maßnahmen auf gesamtstädtischer Ebene und auf Stadtteilebene wurden Maßnahmen angestrebt, die die Risikowahrnehmung, Vorsorge und Selbsthilfefähigkeit von Unternehmen und Bevölkerung stärken können. Daher wurde der Stand der Risikokommunikation in Deutschland für das Projekt aufgearbeitet und eine erste Evaluation von Risikokommunikationswerkzeugen durchgeführt. Der Bericht endet mit einer Kurzfassung des Arbeitsprogramms 2018-2021.
HPI Future SOC Lab
(2015)
Das Future SOC Lab am HPI ist eine Kooperation des Hasso-Plattner-Instituts mit verschiedenen Industriepartnern. Seine Aufgabe ist die Ermöglichung und Förderung des Austausches zwischen Forschungsgemeinschaft und Industrie.
Am Lab wird interessierten Wissenschaftlern eine Infrastruktur von neuester Hard- und Software kostenfrei für Forschungszwecke zur Verfügung gestellt. Dazu zählen teilweise noch nicht am Markt verfügbare Technologien, die im normalen Hochschulbereich in der Regel nicht zu finanzieren wären, bspw. Server mit bis zu 64 Cores und 2 TB Hauptspeicher. Diese Angebote richten sich insbesondere an Wissenschaftler in den Gebieten Informatik und Wirtschaftsinformatik. Einige der Schwerpunkte sind Cloud Computing, Parallelisierung und In-Memory Technologien.
In diesem Technischen Bericht werden die Ergebnisse der Forschungsprojekte des Jahres 2015 vorgestellt. Ausgewählte Projekte stellten ihre Ergebnisse am 15. April 2015 und 4. November 2015 im Rahmen der Future SOC Lab Tag Veranstaltungen vor.
Leptospirosis is a worldwide emerging infectious disease caused by zoonotic bacteria of the genus Leptospira. Numerous mammals, including domestic and companion animals, can be infected by Leptospira spp., but rodents and other small mammals are considered the main reservoir. The annual number of recorded human leptospirosis cases in Germany (2001-2016) was 25-166. Field fever outbreaks in strawberry pickers, due to infection with Leptospira kirschneri serovar Grippotyphosa, were reported in 2007 and 2014. To identify the most commonly occurring Leptospira genomospecies, sequence types (STs), and their small mammal host specificity, a monitoring study was performed during 2010-2014 in four federal states of Germany. Initial screening of kidney tissues of 3,950 animals by PCR targeting the lipl32 gene revealed 435 rodents of 6 species and 89 shrews of three species positive for leptospiral DNA. PCR-based analyses resulted in the identification of the genomospecies L. kirschneri (62.7%), Leptospira interrogans (28.3%), and Leptospira borgpetersenii (9.0%), which are represented by four, one, and two STs, respectively. The average Leptospira prevalence was highest (approximate to 30%) in common voles (Microtus arvalis) and field voles (Microtus agrestis). Both species were exclusively infected with L. kirschneri. In contrast, in bank voles (Myodes glareolus) and yellow-necked mice (Apodemus flavicollis), DNA of all three genomospecies was detected, and in common shrews (Sorex araneus) DNA of L. kirschneri and L. borgpetersenii was identified. The association between individual infection status and demographic factors varied between species; infection status was always positively correlated to body weight. In conclusion, the study confirmed a broad geographical distribution of Leptospira in small mammals and suggested an important public health relevance of common and field voles as reservoirs of L. kirschneri. Furthermore, the investigations identified seasonal, habitat-related, as well as individual influences on Leptospira prevalence in small mammals that might impact public health.
Since the beginning of the 21st century, spotted fever rickettsioses are known as emerging diseases worldwide. Rickettsiae are obligately intracellular bacteria transmitted by arthropod vectors. The ecology of Rickettsia species has not been investigated in detail, but small mammals are considered to play a role as reservoirs. Aim of this study was to monitor rickettsiae in wild small mammals over a period of five years in four federal states of Germany. Initial screening of ear pinna tissues of 3939 animals by Pan-Rick real-time PCR targeting the citrate synthase (gltA) gene revealed 296 rodents of seven species and 19 shrews of two species positive for rickettsial DNA. Outer membrane protein gene (ompB, ompAIV) PCRs based typing resulted in the identification of three species: Rickettsia helvetica (90.9%) was found as the dominantly occurring species in the four investigated federal states, but Rickettsia felis (7.8%) and Rickettsia raoultii (1.3%) were also detected. The prevalence of Rickettsia spp. in rodents of the genus Apodemus was found to be higher (approximately 14%) than in all other rodent and shrew species at all investigated sites. General linear mixed model analyses indicated that heavier (older) individuals of yellow-necked mice and male common voles seem to contain more often rickettsial DNA than younger ones. Furthermore, rodents generally collected in forests in summer and autumn more often carried rickettsial DNA. In conclusion, this study indicated a high prevalence of R. helvetica in small mammal populations and suggests an age-dependent increase of the DNA prevalence in some of the species and in animals originating from forest habitats. The finding of R. helvetica and R. felis DNA in multiple small mammal species may indicate frequent trans-species transmission by feeding of vectors on different species. Further investigations should target the reason for the discrepancy between the high rickettsial DNA prevalence in rodents and the so far almost absence of clinical apparent human infections.
Computerised mirror therapy with Augmented Reflection Technology for early stroke rehabilitation
(2017)
Purpose: New rehabilitation strategies for post-stroke upper limb rehabilitation employing visual stimulation show promising results, however, cost-efficient and clinically feasible ways to provide these interventions are still lacking. An integral step is to translate recent technological advances, such as in virtual and augmented reality, into therapeutic practice to improve outcomes for patients. This requires research on the adaptation of the technology for clinical use as well as on the appropriate guidelines and protocols for sustainable integration into therapeutic routines. Here, we present and evaluate a novel and affordable augmented reality system (Augmented Reflection Technology, ART) in combination with a validated mirror therapy protocol for upper limb rehabilitation after stroke. Results: The results showed that the combination and application of the Berlin Protocol for Mirror Therapy together with ART was feasible for clinical use. This combination was integrated into the therapeutic plan of subacute stroke patients at the two clinical locations where the second part of this research was conducted. Conclusions: Our findings pave the way for using technology to provide mirror therapy in clinical settings and show potential for the more effective use of inpatient time and enhanced recoveries for patients. IMPLICATIONS FOR REHABILITATION Computerised Mirror Therapy is feasible for clinical use Augmented Reflection Technology can be integrated as an adjunctive therapeutic intervention for subacute stroke patients in an inpatient setting Virtual Rehabilitation devices such as Augmented Reflection Technology have considerable potential to enhance stroke rehabilitation
A confocal set-up is presented that improves micro-XRF and XAFS experiment with high-pressure e diamond-anvil cells (DACs) In this experiment a probing volume is defined by the focus of the incoming synchrotron radiation beam and that of a polycapillary X-ray half-lens with a very long working distance, which is placed in front of the fluorescence detector This set-up enhances the quality of the fluorescence and XAFS spectra, and thus the sensitivity for detecting elements at low concentrations. It efficiently suppresses signal from outside the sample chamber, which stems from elastic and inelastic scattering of the incoming beam by the diamond anvils as well as from excitation of fluorescence from the body of the DAC
The iron speciation in hydrous haplotonalitic and haplogranitic silicate glasses was studied using XAFS spectroscopy and transmission electron microscopy (TEM). Spectral features occurring at the main crest of the XANES at the iron K-edge of hydrous glasses indicate contributions to the spectra by iron-moieties present in a more ordered structural environment than found in the dry glass. These differences are also suggested by analysis of the EXAFS. These effects are not completely suppressed even for those samples that were quenched with a higher cooling rate. Strongest differences to the dry glass are observed for a sample that was quenched slowly through the temperature of glass transformation. Crystals (60 to 1500 nm in size) of magnetite, maghemite and another unidentified phase were observed in this sample by TEM, whereas no crystals were found in samples quenched with regular or high cooling rates. In-situ XANES measurements up to 700 degrees C and 500 MPa were performed to reveal the origin (i.e., during synthesis or quench) of the structural differences for those hydrous glasses that do not display any detectable crystallization. The comparison of XANES spectra collected on Fe2+ in water-saturated haplogranitic melt at 700 degrees C and 500 MPa and on Fe2+ in dry melt at 1150 degrees C shows that the local structural environment of Fe2+ in both systems is similar. This indicates that there is no detectable and direct influence of water on the local structure around iron in this type of melt. Hence, the differences observed between hydrous and dry glasses can only be related to artefacts formed during the quench process. (c) 2006 Elsevier B.V. All rights reserved
The crystallization kinetics of silicate liquids were studied experimentally in the system haplogranite-B-Li-H2O, at variable degrees of undercooling and variable water concentration. We investigated the kinetics of nucleation and crystallization of unseeded synthetic hydrous haplogranite with 1 wt % Li2O + 2 center dot 3 wt % B2O3 added (composition C1) and 2 wt % Li2O + 4 center dot 6 wt % B2O3 added (composition C2). Compositions C1 and C2 are simplified representative bulk compositions of Li-rich pegmatites and their highly differentiated cores, respectively. Starting water contents varied between 3 and 9 wt %. With few exceptions, the system remained water-undersaturated. About 86 isothermal runs of 1-60 days duration, grouped in 25 time series of constant temperature and initial H2O content, were carried out at temperatures from 400 to 700A degrees C at 300 MPa, corresponding to variable degrees of undercooling between the liquidus and glass transition. Viscosity measurements indicate that the glass transition for both compositions is below 400A degrees C for 3 wt % water and below 300A degrees C for 6 center dot 5 wt % water. The melts remained virtually crystal free at 400A degrees C, about 100A degrees C and 120A degrees C above the glass transition for compositions C1 and C2, respectively, in experiments up to 30 days long. This result is consistent with the existence of low-temperature, undercooled melts in the crust. At lower values of undercooling the runs crystallized partially, up to about 70% volume fraction. Undercooling and the amount of water are the main factors controlling nucleation and growth rates, and therefore textures. Minerals nucleate and grow sequentially according to mineral-specific nucleation delays. The mineral assemblage started with Li-Al stuffed quartz (in C1) and virgilite (in C2), solid-solutions between quartz and gamma-spodumene. The quartz-like phases were typically followed by spherulitic alkali feldspar-quartz intergrowths, euhedral petalite, and fine-grained muscovite. Nearly pure quartz formed as rims and replacement of metastable virgilite and stuffed quartz, in particular at the boron- and water-rich crystallization front of large feldspar or petalite. With the exception of muscovite, all minerals nucleated heterogeneously, on the capsule wall or on pre-existing minerals, and grew inwards, towards the capsule center. Experimental textures resembled the textures of zoned pegmatites, including skeletal, graphic, unidirectional, radiating, spherulitic, massive, and replacement textures. In some cases, when fluid saturation was reached, miarolitic cavities developed containing euhedral crystals. Although unidirectional growth rates appeared to slow down in time, volumetric rates for stable graphic alkali-feldspar quartz intergrowths and petalite remained constant for up to 60 days and similar to 70% crystallization. Metastable stuffed quartz and virgilite diminished in their growth rates in runs of 30 days or longer, were resorbed in the melt, and were partially replaced by second-generation quartz. Unobstructed, self-sustained crystal growth in conditions of very low nucleation density appears to be the dominant mechanism to form giant pegmatitic crystals, although experimental growth rates are much slower than predicted in nature based on conductive-cooling models.
The volume provides a field-analytical methodology for researching knowledge based sociopolitical processes of transnationalization. Drawing on the seminal work by Pierre Bourdieu, we apply concepts of practice, habitus, and field to phenomena such as cross-national social trajectories, international procedures of evaluation, standardization and certification or supranational political structures. These transnational phenomena form part of general political struggles that legitimate social relationships in and beyond the nation state. Part 1 on "Methodological Foundations" discusses the consequences of Bourdieu's epistemology and methodology for theorizing and investigating transnational phenomena. The contributions show the import of field-theoretical concepts for post-national insights. Part 2 on "Investigating Political Fields" presents exemplary case studies in diverse research areas such as colonial imperialism, international academic rankings, European policy fields, and local school policy. While focusing on their research objects, the contributions also give an insight into the mechanisms involved in processes of transnationalization. The volume is an invitation for sociologists, political scientists and scholars in adjacent research areas to engage with reflexive and relational research practice and to further develop field-theoretical thought.
This introductory essay to the HSR Special Issue “Economists, Politics, and Society” argues for a strong field-theoretical programme inspired by Pierre Bourdieu to research economic life as an integral part of different social forms. Its main aim is threefold. First, we spell out the very distinct Durkheimian legacy in Bourdieu’s thinking and the way he applies it in researching economic phenomena. Without this background, much of what is actually part of how Bourdieu analysed economic aspects of social life would be overlooked or reduced to mere economic sociology. Second, we sketch the main theoretical concepts and heuristics used to analyse economic life from a field perspective. Third, we focus on practical methodological issues of field-analytical research into economic phenomena. We conclude with a short summary of the basic characteristics of this approach and discuss the main insights provided by the contributions to this special issue.