Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators

BACKGROUND: Mutation of the PRDM16 gene has been associated with human cardiomyopathy. The PRDM16 protein is a transcriptional regulator affecting cardiac development via Tbx5 and Hand1 regulating myocardial structure. Biallelic Prdm16 inactivation induces severe cardiac dysfunction with postnatal lethality and hypertrophy in mice. Early pathological events upon Prdm16 inactivation have not been explored. METHODS: This study performed in depth pathophysiological and molecular analysis of male and female Prdm16csp1/wt mice carrying systemic, monoallelic Prdm16 gene inactivation. We systematically assessed early molecular changes with transcriptomics, proteomics, and metabolomics. Kinetic modelling of the cardiac metabolism was undertaken in silico with CARDIOKIN. RESULTS: Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice. Prdm16csp1/wt hearts demonstrate moderate alterations of specific transcripts and protein levels with consistent upregulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre B-cell leukemia transcription factor interacting protein 1 (Pbxip1). The strongest concordant transcriptional upregulation was detected for Prdm16 itself probably by an autoregulatory mechanism. Prdm16csp1/wt cardiac tissue showed reduction of metabolites associated with amino acid as well as glycerol metabolism, glycolysis, and tricarboxylic acid cycle. Global lipid metabolism was also affected with accumulation of triacylglycerides detected in male Prdm16csp1/wt hearts. In addition, Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively. Metabolic modelling in silico suggested lowered fatty acid utilization in male and reduced glucose utilization in female Prdm16csp1/wt cardiac tissue. CONCLUSIONS: Monoallelic Prdm16 mutation restricts cardiac performance in Prdm16csp1/wt mice.Metabolic alterations precede transcriptional dysregulation in Prdm16csp1/wt cardiac tissue. Female Prdm16csp1/wt mice develop a more pronounced phenotype indicating a sexual dimorphism at this early pathological window. This study suggests that metabolic dysregulation is an early event in PRDM16 associated cardiac pathology

Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

Congenital Heart Disease (CHD) affects approximately 7-9 children per 1000 live births. Numerous genetic studies have established a role for rare genomic variants at the copy number variation (CNV) and single nucleotide variant level. In particular, the role of de novo mutations (DNM) has been highlighted in syndromic and non-syndromic CHD. To identify novel haploinsufficient CHD disease genes we performed an integrative analysis of CNVs and DNMs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm (TAA). We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed mutation rate testing for DNMs identified in 2,489 parent-offspring trios. Our combined analysis revealed 21 genes which were significantly affected by rare genomic deletions and/or constrained non-synonymous de novo mutations in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in singletons and small cases series, or show new associations with CHD. In addition, a systems level analysis revealed shared contribution of CNV deletions and DNMs in CHD probands, affecting protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes

Avian collision risk at an offshore wind farm

We have been the first to investigate whether long-lived geese and ducks can detect and avoid a large offshore wind farm by tracking their diurnal migration patterns with radar. We found that the percentage of flocks entering the wind farm area decreased significantly (by a factor 4.5) from pre-construction to initial operation. At night, migrating flocks were more prone to enter the wind farm but counteracted the higher risk of collision in the dark by increasing their distance from individual turbines and flying in the corridors between turbines. Overall, less than 1% of the ducks and geese migrated close enough to the turbines to be at any risk of collision

Neubau eines energieoptimierten Kultur- und Buergerhauses in Denzlingen Abschlussbericht

Fuer das Kultur- und Buergerhaus hat die Gemeinde Denzlingen einen 2-phasigen Realisierungswettbewerb ausgelobt, in dem explizit die Energieoptimierung als Ziel formuliert wurde. Hier wurde ein Richtwert von 30 kWh/m"2/a fuer Raumwaerme formuliert. Entsprechend der seit Jahren aktiv verfolgten Politik der Gemeinde Denzlingen des Klima- und Umweltschutzes sollte das Gebaeude den hoechsten oekologischen Standards genuegen, um unmittelbar einen wesentlichen Beitrag zur Minderung der CO_2-Emissionen zu leisten. Es ging aber nicht darum, eine sogenannte 'Energiesparmaschine' zu bauen, die mit hohem, technischen und finanziellen Aufwand keine Vorbildfunktion fuer vergleichbare Projekte haette. Es ging vielmehr darum, bezogen auf das vorliegende Gebaeudekonzept und dessen Nutzungsansprueche zu schluessigen Loesungen zu gelangen, welche unter oekologischen und oekonomischen Aspekten vorbildhaft und zukunftsweisend sind. (orig.)For the construction of its culture and city hall, the municipality of Denzlingen had started a 2-phase competition, the explicit objective of which was energy optimization. The recommended value for the room temperature was 30 kWh/m2/a. In compliance with the municipality's active policy of protecting climate and environment, the building was to fulfill highest ecological standards in order to make an essential direct contribution to reduce CO2-emissions. The main objective, however, was not to build an ''energy saving machine'' which would have been no model for comparable projects due to its high technical power input and financial expenditures. It was important to achieve logical solutions with regard to the building concept presented and to be able to use these as models and pilots for the future regarding ecological and economical aspects.SIGLEAvailable from TIB Hannover: F02B464 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDeutsche Bundesstiftung Umwelt, Osnabrueck (Germany)DEGerman