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- Butt, Linus, et al.
(författare)
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Super-Resolution Imaging of the Filtration Barrier Suggests a Role for Podocin R229Q in Genetic Predisposition to Glomerular Disease
- 2021
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Ingår i: Journal of the American Society of Nephrology. - : Wolters Kluwer. - 1046-6673 .- 1533-3450. ; 33:1, s. 138-154
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Tidskriftsartikel (refereegranskat)abstract
- Significance Statement Podocin R229Q results from the most frequent missense variant in NPHS2, and its association with FSGS when podocin R229Q is transassociated with a second mutation in NPHS2 is well recognized. However, because results from observational studies are ambiguous and appropriate animal studies are lacking, its isolated pathogenic potency is not entirely clear. In this study, the authors introduced this genetic alteration in mice and assessed the phenotype using super-resolution microscopy and albuminuria measurements. They demonstrated a deleterious effect of the variant on podocyte morphology and on the integrity of the glomerular filtration barrier under basal conditions and after external glomerular injury. Because this finding suggests that this mutation confers a genetic predisposition to glomerular disease, it has implications for a large number of carriers worldwide.Background Diseases of the kidney’s glomerular filtration barrier are a leading cause of end stage renal failure. Despite a growing understanding of genes involved in glomerular disorders in children, the vast majority of adult patients lack a clear genetic diagnosis. The protein podocin p.R229Q, which results from the most common missense variant in NPHS2, is enriched in cohorts of patients with FSGS. However, p.R229Q has been proposed to cause disease only when transassociated with specific additional genetic alterations, and population-based epidemiologic studies on its association with albuminuria yielded ambiguous results.Methods To test whether podocin p.R229Q may also predispose to the complex disease pathogenesis in adults, we introduced the exact genetic alteration in mice using CRISPR/Cas9-based genome editing (PodR231Q). We assessed the phenotype using super-resolution microscopy and albuminuria measurements and evaluated the stability of the mutant protein in cell culture experiments.Results Heterozygous PodR231Q/wild-type mice did not present any overt kidney disease or proteinuria. However, homozygous PodR231Q/R231Q mice developed increased levels of albuminuria with age, and super-resolution microscopy revealed preceding ultrastructural morphologic alterations that were recently linked to disease predisposition. When injected with nephrotoxic serum to induce glomerular injury, heterozygous PodR231Q/wild-type mice showed a more severe course of disease compared with Podwild-type/wild-type mice. Podocin protein levels were decreased in PodR231Q/wild-type and PodR231Q/R231Q mice as well as in human cultured podocytes expressing the podocinR231Q variant. Our in vitro experiments indicate an underlying increased proteasomal degradation.Conclusions Our findings demonstrate that podocin R231Q exerts a pathogenic effect on its own, supporting the concept of podocin R229Q contributing to genetic predisposition in adult patients.
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- Dubash, Navroz K., et al.
(författare)
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Developments in national climate change mitigation legislation and strategy
- 2013
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Ingår i: Climate Policy. - London : Taylor & Francis. - 1469-3062 .- 1752-7457. ; 13:6, s. 649-664
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Tidskriftsartikel (refereegranskat)abstract
- The results are presented from a survey of national legislation and strategies to mitigate climate change covering almost all United Nations member states between 2007 and 2012. This data set is distinguished from the existing literature in its breadth of coverage, its focus on national policies (rather than international pledges), and on the use of objective metrics rather than normative criteria. The focus of the data is limited to national climate legislation and strategies and does not cover subnational or sectoral measures. Climate legislation and strategies are important because they can: enhance incentives for climate mitigation; provide mechanisms for mainstreaming; and provide a focal point for actors. Three broad findings emerge. First, there has been a substantial increase in climate legislation and strategies between 2007 and 2012: 67% of global GHG emissions are now under national climate legislation or strategy compared to 45% in 2007. Second, there are substantial regional effects to the patterns, with most increases in non-Annex I countries, particularly in Asia and Latin America. Third, many more countries have adopted climate strategies than have adopted climate legislation between 2007 and 2012. The article concludes with recommendations for future research.Policy relevance The increase in climate legislation and strategy is significant. This spread suggests that, at the national level, there is some movement in reshaping climate governance despite the relatively slow pace of global negotiations, although the exact implications of this spread require further research on stringency of actions and their implementation. Asia and Latin America represent the biggest improvements, while OECD countries, which start from a high base, remain relatively stagnant. Implications of regional patterns are further refined by an analysis by emissions, which shows that some areas of low levels of legislation and strategy are also areas of relatively low emissions. A broad trend toward an emphasis on strategies rather than legislation, with the significant exception of China, calls for enhanced research into the practical impact of national non-binding climate strategies versus binding legislation on countries' actual emissions over time.
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- Höhne, Markus, et al.
(författare)
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Beschäftigungsprognosen auf Basis amtlicher Firmendaten als Instrument einer handlungsorientierten Politikberatung am Beispiel Brandenburg
- 2007
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Ingår i: Quarterly Journal of Economic Research. - : Duncker & Humblot. ; 76:3, s. 88-112
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Tidskriftsartikel (refereegranskat)abstract
- Das in diesem Artikel beschriebene ökonometrische Prognosemodell stellteinen innovativen Ansatz der Nutzung von amtlichen Firmendaten (Mikrodaten) für die Vorhersagevon sektoral bzw. regional differenzierten Fachkräftebedarfen dar. Ziel unseres dynamischen Modellsist eine kurzfristig orientierte Prognose des Beschäftigungsverlaufs – mit einem Horizont von 12 bis24 Monaten – unter Berücksichtigung der Umsatz-, Auftrags-, Lohn- sowie Exportentwicklung amBeispiel Brandenburger Metallwirtschaft zu ermitteln. Die Grundlage für das Prognosemodell bildetein Betriebspanel aus dem „Monatsbericht für Betriebe des Verarbeitenden Gewerbes sowie desBergbaus und der Gewinnung von Steinen und Erden“. Grundsätzlich kann festgestellt werden, dassdas Modell als ein geeignetes Prognoseinstrument der kurzfristigen Beschäftigungsentwicklung füreine handlungsorientierte Politikberatung anzusehen ist.
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