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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.
Myriapods (e. g., centipedes and millipedes) display a simple homonomous body plan relative to other arthropods. All members of the class are terrestrial, but they attained terrestriality independently of insects. Myriapoda is the only arthropod class not represented by a sequenced genome. We present an analysis of the genome of the centipede Strigamia maritima. It retains a compact genome that has undergone less gene loss and shuffling than previously sequenced arthropods, and many orthologues of genes conserved from the bilaterian ancestor that have been lost in insects. Our analysis locates many genes in conserved macro-synteny contexts, and many small-scale examples of gene clustering. We describe several examples where S. maritima shows different solutions from insects to similar problems. The insect olfactory receptor gene family is absent from S. maritima, and olfaction in air is likely effected by expansion of other receptor gene families. For some genes S. maritima has evolved paralogues to generate coding sequence diversity, where insects use alternate splicing. This is most striking for the Dscam gene, which in Drosophila generates more than 100,000 alternate splice forms, but in S. maritima is encoded by over 100 paralogues. We see an intriguing linkage between the absence of any known photosensory proteins in a blind organism and the additional absence of canonical circadian clock genes. The phylogenetic position of myriapods allows us to identify where in arthropod phylogeny several particular molecular mechanisms and traits emerged. For example, we conclude that juvenile hormone signalling evolved with the emergence of the exoskeleton in the arthropods and that RR-1 containing cuticle proteins evolved in the lineage leading to Mandibulata. We also identify when various gene expansions and losses occurred. The genome of S. maritima offers us a unique glimpse into the ancestral arthropod genome, while also displaying many adaptations to its specific life history.
Fluorescent molecular probes for metal ions have a raft of potential applications in chemistry and biomedicine. We report the synthesis and photophysical characterisation of 1,8-disubstituted-cyclam/naphthalimide conjugates and their zinc complexes. An efficient synthesis of 1,8-bis-(2-azidoethyl)cyclam has been developed and used to prepare 1,8-disubstituted triazolyl-cyclam systems, in which the pendant group is connected to triazole C4. UV/Vis and fluorescence emission spectra, zinc binding experiments, fluorescence quantum yield and lifetime measurements and pH titrations of the resultant bis-naphthalimide ligand elucidate a complex pattern of photophysical behaviour. Important differences arise from the inclusion of two fluorophores in the one probe and from the variation of triazole substitution pattern (dye at C4 vs. N1). Introducing a second fluorophore greatly extends fluorescence lifetimes, whereas the altered substitution pattern at the cyclam amines exerts a major influence on fluorescence output and metal binding. Crystal structures of two key zinc complexes evidence variations in triazole coordination that mirror the solution-phase behaviour of these systems.
Eine verbesserte Zusammenarbeit und Abstimmung von Fachwissenschaft, Fachdidaktik, Bildungswissenschaften und schulpraktischen Lernorten ist einer der Förderbereiche der „Qualitätsoffensive Lehrerbildung“. Zahlreiche der geförderten Projekte haben für dieses Handlungsfeld im Bereich Vernetzung von Fachwissenschaft, Fachdidaktik und Bildungswissenschaften hochschulspezifische Maßnahmen konzipiert und umgesetzt.
Der vorliegende Tagungsband beinhaltet Beiträge von 15 entsprechenden Projekten, von denen sieben anlässlich von zwei standortübergreifenden Projekt-Tagungen in Hannover und Potsdam vorgestellt und in Workshops diskutiert wurden. Insgesamt geben die Beiträge einen theoretisch fundierten und gleichzeitig praxisorientierten Überblick über aktuelle Ansätze und Konzepte zur besseren Vernetzung fachwissenschaftlicher, fachdidaktischer und bildungswissenschaftlicher Studienanteile im Lehramtsstudium. Dargestellt werden Projektarbeiten der Hochschulen, die auf verschiedenen Ebenen wirksam werden (curricular-inhaltliche Ebene, kollegiale Ebene, hochschul-strukturelle Ebene). Die Maßnahmen sind so beschrieben, dass sie als Grundlage für einen Transfer auf andere Fächer bzw. andere Standorte genutzt werden können.
Die Beiträge richten sich an alle Lehrenden im Bereich der Lehramtsbildung sowie sonstige Akteure im Bereich der Lehr- und Qualitätsentwicklung an den Universitäten. Sie alle können den beschriebenen Konzepten und Umsetzungsformaten transferierbare Ideen und Impulse entnehmen.
The effects of climate and topography on soil physico-chemical and microbial parameters were studied along an extensive latitudinal climate gradient in the Coastal Cordillera of Chile (26 degrees-38 degrees S). The study sites encompass arid (Pan de Azucar), semiarid (Santa Gracia), mediterranean (La Campana) and humid (Nahuelbuta) climates and vegetation, ranging from arid desert, dominated by biological soil crusts (biocrusts), semiarid shrubland and mediterranean sclerophyllous forest, where biocrusts are present but do have a seasonal pattern to temperate-mixed forest, where biocrusts only occur as an early pioneering development stage after disturbance. All soils originate from granitic parent materials and show very strong differences in pedogenesis intensity and soil depth. Most of the investigated physical, chemical and microbiological soil properties showed distinct trends along the climate gradient. Further, abrupt changes between the arid northernmost study site and the other semi-arid to humid sites can be shown, which indicate non-linearity and thresholds along the climate gradient. Clay and total organic carbon contents (TOC) as well as Ah horizons and solum depths increased from arid to humid climates, whereas bulk density (BD), pH values and base saturation (BS) decreased. These properties demonstrate the accumulation of organic matter, clay formation and element leaching as key-pedogenic processes with increasing humidity. However, the soils in the northern arid climate do not follow this overall latitudinal trend, because texture and BD are largely controlled by aeolian input of dust and sea salts spray followed by the formation of secondary evaporate minerals. Total soil DNA concentrations and TOC increased from arid to humid sites, while areal coverage by biocrusts exhibited an opposite trend. Relative bacterial and archaeal abundances were lower in the arid site, but for the other sites the local variability exceeds the variability along the climate gradient. Differences in soil properties between topographic positions were most pronounced at the study sites with the mediterranean and humid climate, whereas microbial abundances were independent on topography across all study sites. In general, the regional climate is the strongest controlling factor for pedogenesis and microbial parameters in soils developed from the same parent material. Topographic position along individual slopes of limited length augmented this effect only under humid conditions, where water erosion likely relocated particles and elements downward. The change from alkaline to neutral soil pH between the arid and the semi-arid site coincided with qualitative differences in soil formation as well as microbial habitats. This also reflects non-linear relationships of pedogenic and microbial processes in soils depending on climate with a sharp threshold between arid and semi-arid conditions. Therefore, the soils on the transition between arid and semi-arid conditions are especially sensitive and may be well used as indicators of long and medium-term climate changes. Concluding, the unique latitudinal precipitation gradient in the Coastal Cordillera of Chile is predestined to investigate the effects of the main soil forming factor - climate - on pedogenic processes.
From north to south, denudation rates from cosmogenic nuclides are similar to 10 t km(-2) yr(-1) at the arid Pan de Aziicar site, similar to 20 t km(2) yr(-1) at the semi-arid site of Santa Gracia, -60 t km(-2) yr(-1) at the Mediterranean climate site of La Campana, and similar to 30 t km(-2) yr(-1) at the humid site of Nahuelbuta. A and B horizons increase in thickness and elemental depletion or enrichment increases from north (similar to 26 degrees S) to south (similar to 38 degrees S) in these horizons. Differences in the degree of chemical weathering, quantified by the chemical depletion fraction (CDF), are significant only between the arid and sparsely vegetated site and the other three sites. Differences in the CDF between the sites, and elemental depletion within the sites are sometimes smaller than the variations induced by the bedrock heterogeneity. Microbial abundances (bacteria and archaea) in saprolite substantially increase from the arid to the semi-arid sites. With this study, we provide a comprehensive dataset characterizing the Critical Zone geochemistry in the Chilean Coastal Cordillera. This dataset confirms climatic controls on weathering and denudation rates and provides prerequisites to quantify the role of biota in future studies.
Recent technological developments have increased the number of variables being monitored in lakes and reservoirs using automatic high frequency monitoring (AHFM). However, design of AHFM systems and posterior data handling and interpretation are currently being developed on a site-by-site and issue-by-issue basis with minimal standardization of protocols or knowledge sharing. As a result, many deployments become short-lived or underutilized, and many new scientific developments that are potentially useful for water management and environmental legislation remain underexplored. This Critical Review bridges scientific uses of AHFM with their applications by providing an overview of the current AHFM capabilities, together with examples of successful applications. We review the use of AHFM for maximizing the provision of ecosystem services supplied, by lakes and reservoirs (consumptive and non consumptive uses, food production, and recreation), and for reporting lake status in the EU Water Framework Directive. We also highlight critical issues to enhance the application of AHFM, and suggest the establishment of appropriate networks to facilitate knowledge sharing and technological transfer between potential users. Finally, we give advice on how modern sensor technology can successfully be applied on a larger scale to the management of lakes and reservoirs and maximize the ecosystem services they provide.
Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting-state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS-or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between CT and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research.
Portal alumni
(2010)
Das gerade begonnene Jahr wird für die Universität Potsdam ein besonderes werden, ist es doch das 20. Jahr ihres Bestehens. Auf das Erreichte ist die Hochschule mit Recht stolz. Die Universität Potsdam ist für Studieninteressierte ungebrochen attraktiv, was die steigenden Bewerberzahlen zeigen. Allein im vergangenen Jahr haben Uni-Wissenschaftler knapp 42 Millionen Euro Drittmittel eingeworben und die Liste gemeinsamer Verbundprojekte mit außeruniversitären Forschungseinrichtungen der Region wächst weiter. Zu den Erfolgen zählt weiterhin auch die steigende Anzahl von Absolventinnen und Absolventen der Hochschule.
In die Gründung der Universität Potsdam am 15. Juli 1991 flossen zwei Vorgängereinrichtungen ein. Die wichtigste war die Brandenburgische Landeshochschule, vorher Pädagogische Hochschule, die über vier Jahrzehnte hinweg Lehrerinnen und Lehrer ausgebildet hat. Die Lehrerbildung hat auch für die Universität Potsdam profilbildenden Charakter, denn allein vier der fünf Fakultäten sind an der Lehrerbildung beteiligt und haben Generationen von jungen Leuten für den Lehrerberuf qualifiziert. Heute ist das Ziel aller an der Lehrerbildung Beteiligten, eine professionsorientierte, qualitativ hochwertige Lehrerbildung zu sichern, die sich an den Kompetenzen Erziehen, Unterrichten, Beraten, Betreuen, Innovieren und Organisieren orientiert. Eine besondere Herausforderung sieht die Universität Potsdam dabei in der Vernetzung von wissenschaftlicher Forschung und Lehrerbildung.
Portal alumni stellt in der hier vorliegenden Ausgabe im Jubiläumsjahr zwölf Absolventen der Lehrerbildung vor. Sie berichten aus jeweils individueller Perspektive, wie sie ihr Studium an der Universität Potsdam erlebt haben und wie es sie geprägt hat. Und natürlich stellt das Magazin zugleich aktuelle Entwicklungstrends in der Lehrerbildung vor. Wie in allen Heften zuvor berichten wir von der Alumni-Arbeit des Jahres 2010 und stellen Höhepunkte des Unialltags vor. Wir wünschen Ihnen eine unterhaltsame Lektüre und sind gespannt auf Ihr Feedback zu diesem Heft.
Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Regulation of respiration and fermentation to control the plant internal oxygen concentration
(2009)
Plant internal oxygen concentrations can drop well below ambient even when the plant grows under optimal conditions. Using pea (Pisum sativum) roots, we show how amenable respiration adapts to hypoxia to save oxygen when the oxygen availability decreases. The data cannot simply be explained by oxygen being limiting as substrate but indicate the existence of a regulatory mechanism, because the oxygen concentration at which the adaptive response is initiated is independent of the actual respiratory rate. Two phases can be discerned during the adaptive reaction: an initial linear decline of respiration is followed by a nonlinear inhibition in which the respiratory rate decreased progressively faster upon decreasing oxygen availability. In contrast to the cytochrome c pathway, the inhibition of the alternative oxidase pathway shows only the linear component of the adaptive response. Feeding pyruvate to the roots led to an increase of the oxygen consumption rate, which ultimately led to anoxia. The importance of balancing the in vivo pyruvate availability in the tissue was further investigated. Using various alcohol dehydrogenase knockout lines of Arabidopsis (Arabidopsis thaliana), it was shown that even under aerobic conditions, alcohol fermentation plays an important role in the control of the level of pyruvate in the tissue. Interestingly, alcohol fermentation appeared to be primarily induced by a drop in the energy status of the tissue rather than by a low oxygen concentration, indicating that sensing the energy status is an important component of optimizing plant metabolism to changes in the oxygen availability.
Background: A direct pharmacological stimulation of soluble guanylate cyclase (sGC) is an emerging therapeutic approach to the management of various cardiovascular disorders associated with endothelial dysfunction. Novel sGC stimulators, including riociguat (BAY 63-2521), have a dual mode of action: They sensitize sGC to endogenously produced nitric oxide (NO) and also directly stimulate sGC independently of NO. Little is known about their effects on tissue remodeling and degeneration and survival in experimental malignant hypertension.
Methods and Results: Mortality, hemodynamics and biomarkers of tissue remodeling and degeneration were assessed in Dahl salt-sensitive rats maintained on a high salt diet and treated with riociguat (3 or 10 mg/kg/d) for 14 weeks. Riociguat markedly attenuated systemic hypertension, improved systolic heart function and increased survival from 33% to 85%. Histological examination of the heart and kidneys revealed that riociguat significantly ameliorated fibrotic tissue remodeling and degeneration. Correspondingly, mRNA expression of the pro-fibrotic biomarkers osteopontin (OPN), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and plasminogen activator inhibitor-1 (PAI-1) in the myocardium and the renal cortex was attenuated by riociguat. In addition, riociguat reduced plasma and urinary levels of OPN, TIMP-1, and PAI-1.
Conclusions: Stimulation of sGC by riociguat markedly improves survival and attenuates systemic hypertension and systolic dysfunction, as well as fibrotic tissue remodeling in the myocardium and the renal cortex in a rodent model of pressure and volume overload. These findings suggest a therapeutic potential of sGC stimulators in diseases associated with impaired cardiovascular and renal functions.
Ligands incorporating a tetraazamacrocycle receptor, a 'click'-derived triazole and a 1,8-naphthalimide fluorophore have proven utility as probes for metal ions. Three new cyclam-based molecular probes are reported, in which a piperidinyl group has been introduced at the 4-position of the naphthalimide fluorophore. These compounds have been synthesized using the copper(I)-catalyzed azide-alkyne Huisgen cycloaddition and their photophysical properties studied in detail. The alkylamino group induces the expected red-shift in absorption and emission spectra relative to the simple naphthalimide derivatives and gives rise to extended fluorescence lifetimes in aqueous buffer. The photophysical properties of these systems are shown to be highly solvent-dependent. Screening the fluorescence responses of the new conjugates to a wide variety of metal ions reveals significant and selective fluorescence quenching in the presence of copper(II), yet no fluorescence enhancement with zinc(II) as observed previously for the simple naphthalimide derivatives. Reasons for this different behaviour are proposed. Cytotoxicity testing shows that these new cyclam-triazole-dye conjugates display little or no toxicity against either DLD-1 colon carcinoma cells or MDA-MB-231 breast carcinoma cells, suggesting a potential role for these and related systems in biological sensing applications.
The fluorescence response of a set of cyclam-triazole-dye ligands is controlled by the appended dye, but simple reversal of the triazole topology affords a novel probe for Zn2+ with a longer fluorescence lifetime and higher fluorescence quantum yield upon Zn2+ binding (<tau t > = 2.0 ns, Phi(f) = 0.76).